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Purpose: To compare, between Alzheimer's disease (AD) patients and healthy individuals, corneal subbasal nerve plexus (CSNP) parameters and corneal sensitivities. Methods: Twenty-two patients who were followed up with Alzheimer's disease (Alzheimer's group) and 18 age- and gender-matched healthy individuals (control group) were included in this cross-sectional study. CSNP parameters, including nerve fiber length (NFL), nerve fiber density (NFD), and nerve branch density (NBD), were evaluated using in vivo confocal microscopy. Corneal sensitivity was evaluated using a Cochet-Bonnet esthesiometer. The results were compared between the two groups. Results: In the Alzheimer's group, NFL was 12.2 (2.4) mm/mm2, NFD was 12.5 [3.1] fibers/mm2, and NBD was 29.7 [9.37] branches/mm2. In the control group, NFL was 16.5 (2.0) mm/mm2, NFD was 25.0 [3.13] fibers/mm2, and NBD was 37.5 [10.9] branches/mm2. All three parameters were significantly lower in the Alzheimer's group compared to the control group (p < 0.001, p < 0.001, and p = 0.001, respectively). Similarly, corneal sensitivity was significantly lower in the Alzheimer's group (55.0 [5.0] mm) compared to the control group (60.0 [5.0] mm) (p < 0.001). Conclusion: We determined that, in AD, corneal sensitivity decreases significantly, in parallel with the decrease in corneal nerves. Changes in the corneal nerve plexus and a decrease in corneal sensitivity may be used in the early diagnosis and follow-up of AD. In addition, ocular surface problems secondary to these changes should also be kept in mind. [ABSTRACT FROM AUTHOR]

Qiaoling Wei,1– 3,&ast; Liangliang Niu,1– 3,&ast; Xianjin Zhou,4 Han Chen,1,2 Rui Jiang1– 3 1Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, People’s Republic of China; 3Ocular Trauma Center, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 4Department of Ophthalmology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui Jiang; Han Chen, Tel +86-21-64377134, Fax +86-21-6477134, Email 2jiang@163.com; avnus@163.comPurpose: To evaluate the effects of retinal surgery on the ocular surface and corneal subbasal nerve plexus (SNP).Methods: Ninety-eight patients undergoing 23-gauge pars plana vitrectomy for various vitreoretinal disorders were prospectively studied. We collected detailed operative and perioperative data, measuring dry eye syndrome (DED) severity and Ocular Surface Disease Index (OSDI) scores before surgery and at postoperative intervals. In vivo confocal microscopy (IVCM) quantified SNP and dendritic cell (DC) densities.Results: Fifty-three patients were analyzed. Post-surgery, OSDI scores rose from a baseline of 5.5 ± 3.5 to 12.24 ± 6.5 at one month, later reducing to 7.8 ± 4.0 after a year. DED severity increased from 0.6 ± 0.6 initially to 1.6 ± 0.6 at three months, returning to near baseline (0.9 ± 0.6) one year after surgery. DC densities increased notably by the third (58.85 ± 75.6 cells/mm²) and ninth (59.95 ± 86 cells/mm²) postoperative months, especially in patients undergoing combined phacoemulsification, vitrectomy, and C3F8 gas tamponade. SNP parameters, particularly nerve fiber density and length, showed significant declines one month post-surgery, not recovering to baseline levels within a year. Fiber density dropped from 19.06 ± 8.3 fibers/mm² preoperatively to 4.68 ± 4.8 fibers/mm² at one month, partially recovering to 10.64 ± 8.2 fibers/mm² at twelve months. Fiber length decreased from 13.31 ± 3.2 mm/mm² to 6.86 ± 3.4 mm/mm² at one month, later improving to 9.81 ± 4.5 mm/mm² at twelve months, notably in patients with silicone oil (SiO2) tamponade.Conclusion: Retinal surgery, especially when combined with phacoemulsification and C3F8 or SiO2 tamponade, significantly affects ocular surface integrity and SNP density, with these changes lasting up to a year. Expanded studies with more patients and longer follow-up, using finer 25- and 27-gauge vitrectomy tools, are recommended to confirm and extend these findings.Keywords: corneal subbasal nerve plexus, ocular surface, retinal surgical procedures, confocal microscopy, dry eye syndrome after vitrectomy, intraocular surgery

Objective: To determine whether there is a difference in corneal sensitivity and corneal subbasal nerve plexus (CSNP) morphology in cataractous dogs with diabetes mellitus (DM) versus without DM. Animals studied: Twenty six domestic dogs with cataracts of various breeds presented for phacoemulsification, 13 with DM and 13 without DM. Procedure: The inclusion criteria for the study were dogs with bilateral cataracts and no clinical evidence of corneal disease. The diabetic group had documented hyperglycemia and was currently treated with insulin. The non-diabetic group had no evidence of DM on examination and bloodwork. Complete ophthalmic examination, corneal esthesiometry, and in vivo confocal microscopy of the CSNP was performed for both eyes of each dog. The CSNP was evaluated using a semi-automated program and statistically analyzed. Results: The mean (±SD) CSNP fiber length was significantly decreased in diabetic (3.8 ± 3.0 mm/mm2) versus non-diabetic (6.7 ± 1.9 mm/mm2) dogs. Likewise, the mean (±SD) fiber density was significantly decreased in diabetic (8.3 ± 3.1 fibers/mm2) versus non-diabetic (15.5 ± 4.9 fibers/mm2) dogs. The corneal touch threshold was significantly reduced in diabetic (2.1 ± 0.8 cm) versus non-diabetic (2.8 ± 0.4 cm) dogs. There was a non-significant trend towards subclinical keratitis in diabetic (9/13) versus non-diabetic (4/13) dogs. Conclusions: Morphological and functional abnormalities of the CSNP were present in dogs with DM, including decreased fiber length, fiber density, and corneal sensitivity. These findings are consistent with diabetic neuropathy and could contribute to clinically significant corneal complications after cataract surgery. [ABSTRACT FROM AUTHOR]

In vivo corneal confocal microscopy (IVCM) allows the immediate analysis of the corneal nerve quantity and morphology. This method became, an indispensable tool for the tropism examination, as it evaluates the small fiber plexus in the cornea. The IVCM provides us with direct information on the health of the sub-basal nerve plexus and indirectly on the peripheral nerve status. It is an important tool used to investigate peripheral polyneuropathies. Small-fiber neuropathy (SFN) is a group of neurological disorders characterized by neuropathic pain symptoms and autonomic complaints due to the selective involvement of thinly myelinated Aδ-fibers and unmyelinated C-fibers. Accurate diagnosis of SFN is important as it provides a basis for etiological work-up and treatment decisions. The diagnosis of SFN is sometimes challenging as the clinical picture can be difficult to interpret and standard electromyography is normal. In cases of suspected SFN, measurement of intraepidermal nerve fiber density through a skin biopsy and/or analysis of quantitative sensory testing can enable diagnosis. The purpose of the present review is to summarize the current knowledge about corneal nerves in different SFN. Specifically, we explore the correlation between nerve density and morphology and type of SFN, disease duration, and follow-up. We will discuss the relationship between cataracts and refractive surgery and iatrogenic dry eye disease. Furthermore, these new paradigms in SFN present an opportunity for neurologists and clinical specialists in the diagnosis and monitoring the peripheral small fiber polyneuropathies. [ABSTRACT FROM AUTHOR]

Introduction: The assessment of the corneal nerve fibre plexus with corneal confocal microscopy (CCM) is an upcoming but still experimental method in the diagnosis of early stage diabetic peripheral neuropathy (DPN). Using an innovative imaging technique—Heidelberg Retina Tomograph equipped with the Rostock Cornea Module (HRT-RCM) and EyeGuidance module (EG)—we were able to look at greater areas of subbasal nerve plexus (SNP) in order to increase the diagnostic accuracy. The aim of our study was to evaluate the usefulness of EG instead of single image analysis in diagnosis of early stage DPN. Methods: This prospective study was performed on 60 patients with type 2 diabetes mellitus, classified equally into two subgroups based on neuropathy deficient score (NDS): patients without DPN (group 1) or with mild DPN (group 2). The following parameters were analysed in the two subgroups: corneal nerve fibre length (CNFL; mm/mm2), corneal nerve fibre density (CNFD; no./mm2), corneal nerve branch density (CNBD; no./mm2). Furthermore, we compared the data calculated with the novel mosaic, EG-based method with those received from single image analysis using different quantification tools. Results: Using EG we did not find a significant difference between group 1 and group 2: CNFL (16.81 ± 5.87 mm/mm2 vs. 17.19 ± 7.19 mm/mm2, p = 0.895), CNFD (254.05 ± 115.36 no./mm2 vs. 265.91 ± 161.63 no./mm2, p = 0.732) and CNBD (102.68 ± 62.28 no./mm2 vs. 115.38 ± 96.91 no./mm2, p = 0.541). No significant difference between the EG method of analysing the SNP and the single image analysis of 10 images per patient was detected. Conclusion: On the basis of our results it was not possible to differentiate between early stages of large nerve fibre DPN in patients with type 2 diabetes mellitus via SNP analysis. To improve sensitivity and specificity of this method newer technologies are under current evaluation. Trial Registration: ClinicalTrials.gov Identifier NCT05326958. [ABSTRACT FROM AUTHOR]

Featured Application: Characterization of the corneal nerve fibers is gaining popularity for objective assessment of anterior segment anomalies such as dry eye disease. Confocal microscopy provides high-resolution imaging of the sub-basal plexus; thus, several parameters such as corneal length, density or tortuosity can be analyzed. However, the analysis of these images is usually performed based on manual or semiautomated methods, many of which are subjective and time consuming. In this work, a fully automated tortuosity corneal nerve fiber analysis method is proposed. This new tool may be very useful to obtain an accurate evaluation of nerve alterations, to monitor changes over time and/or in response to treatment, to ensure comparisons across different studies or even to improve the diagnosis of ocular surface diseases. An automated tool for corneal nerve fiber tortuosity quantification from in vivo confocal microscopy (IVCM) is described and evaluated. The method is a multi-stage process based on the splitting of the corneal nerve fibers into individual segments, whose endpoints are an extreme or intersection of white pixels on a binarized image. Individual segment tortuosity is quantified in terms of the arc-chord ratio. Forty-three IVCM images from 43 laser-assisted in situ keratomileusis (LASIK) surgery patients were used for evaluation. Images from symptomatic dry eye disease (DED) post-LASIK patients, with ( n = 16 ) and without ( n = 7 ) ocular pain, and non-DED post-LASIK controls ( n = 20 ) were assessed. The automated tortuosity measure was compared to a manual grading one, obtaining a moderate correlation (Spearman's rank correlation coefficient = 0.49 , p = 0.0008 ). The new tortuosity index was significantly higher in post-LASIK patients with ocular pain than in control patients ( p = 0.001 ), while no significant differences were detected with manual measurement ( p > 0.28 ). The tortuosity quantification was positively correlated with the ocular surface disease index (OSDI) and a numeric rating scale (NRS) assessing pain ( p = 0.0012 and p = 0.0051 , respectively). The results show good performance of the proposed automated methodology for the evaluation of corneal nerve tortuosity. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate the interobserver and intraobserver reliability of quantitative corneal subbasal nerve plexus (CSNP) analyses using semi-automated software. Patients and Methods: Forty volunteers who applied to the Ophthalmology Department of the Necmettin Erbakan University Meram Faculty of Medicine between 20 December 2021 and 20 January 2022 were enrolled in the study. Images showing CSNP were obtained from the right eyes of the participants by using Heidelberg Retina Tomograph III with Rostock Cornea Module. Three best quality images were selected from each case. NeuronJ plugin for ImageJ software was used to trace nerve fibers and calculate nerve fiber length (NFL), nerve fiber density (NFD), and nerve branch density (NBD). All these measurements were performed by two different observers, and repeated for the second time by one of the observers with an interval of one week, and interobserver and intraobserver reliability were determined using the intraclass correlation coefficient (ICC). Results: The mean age of 40 participants (12 female and 28 male) was 34.70±5.86 years. The ICCs for interobserver reproducibility were 0.967 (95% CI 0.939-0.982) for NFL, 0.826 (95% CI 0.696-0.904) for NFD, and 0.949 (95% CI 0.906-0.973) for NBD indicating good to excellent reliability. The ICCs for intraobserver repeatibility were 0.964 (95% CI 0.932-0.981) for NFL, 0.803 (95% CI 0.657-0.891) for NFD, and 0.890 (95% CI 0.802-0.941) for NBD indicating good to excel lent reliability. Conclusion: Quantitative CSNP analyzes using semi-automated software have high interobserver and intraobserver reliability and can therefore be used in both clinical practice and clinical studies for detection and follow-up of corneal nerves' well-being, damage, and evaluation of response to treatment. [ABSTRACT FROM AUTHOR]

PurposeInvestigate the correlation and agreement between the results of semiautomated and fully automated quantitative analysis of the corneal sub-basal nerve plexus (SNP) in patients with dry eye disease (DED) with ocular pain using in vivo confocal microscopy (IVCM).MethodA total of 50 voluntary participants were enrolled in this study, i.e., 25 DED patients with ocular pain and 25 healthy controls. Each patient underwent an evaluation of ocular symptoms that utilized: the Ocular Surface Disease Index (OSDI), the Ocular Pain Assessment Survey (OPAS), the tear film breakup time (TBUT) test, the Schirmer test, corneal staining, and IVCM. Five SNP images of the cornea of each eye were selected and analyzed using a semiautomated analysis software (NeuronJ) and a fully automated method (ACCMetrics) to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL).ResultsThe intraclass correlation coefficient (ICC) of the CNFD (0.460 [0.382–0.532], p < 0.001), CNBD (0.608 [0.545–0.665], p < 0.001), and CNFL (0.851 [0.822–0.875], p < 0.001) represents the repeatability and consistency of measurements by the NeuronJ and ACCMetrics software. The CNFL values (r = 0.881, p < 0.001) obtained using the two methods have extremely high correlation, and similarly, the CNFD values (r = 0.669, p < 0.001) and CNBD values (r = 0.703, p < 0.001) are highly correlated. The CNFL had the biggest area under the curve (AUC; 0.747 [0.700–0.793], p < 0.001) when using ACCMetrics. In DED patients with ocular pain, the mean CNFD values for semiautomated and fully automated quantization were 23.5 ± 8.1 and 23.8 ± 8.6 n/mm2; the mean CNBD values were 46.0 ± 21.3, 35.7 ± 23.3 n/mm2; and the mean CNFL values were 19.3 ± 4.3 and 15.2 ± 3.8 mm/mm2, which were significantly lower than healthy subjects (p < 0.001).ConclusionThere is a significant correlation between the measurements obtained via ACCMetrics and NeuronJ, especially for CNFL, which can be considered as the primary indicator in the diagnosis of DED with ocular pain. The SNP of the disease was significantly lower than that of healthy subjects.

Purpose/Aim: Our study aims to evaluate corneal subbasal nerve plexus morphology by in vivo corneal confocal microscopy (CCM) in Multiple Sclerosis (MS) patients and to explore its potential ability to distinguish between MS patients and healthy subjects. Materials and methods: Cross-sectional study, including 60 MS patients and 22 healthy subjects. Expanded Disability Status Scale (EDSS) was used to assess neurological disability. All participants underwent full ophthalmology evaluation, CCM and optical coherence tomography (OCT). Corneal nerve fibre density (CNFD), branch density (CNBD), fibre length (CNFL) and fibre tortuosity (CNFT) were analysed. Generalized additive regression models were used to analyse the data. Results: Compared to controls, MS patients had lower CNFD, CNBD and CNFL (p <.001) and higher CNFT (p =.002). The area under the ROC curve to distinguish MS patients from healthy controls with CNFD and CNBD was 0.84 (95%CI: 0.75 to 0.93; 95%CI: 0.75 to 0.92, respectively). A nonlinear association between EDSS and CNFD was found, with an initial density increase followed by a significant decrease until more severe disability status. EDSS was associated with CNFL and CNBD, with values being significantly lower for patients with an EDSS > 2.5 (−2.06 mm/mm2; 95%CI: −3.84 to −0.28; p =.027 and −8.70 branches/mm2; 95%CI: −14.69 to −2.71; p =.006, respectively). An optic neuritis (ON) history did not influence CCM parameters. Conclusions: Our results confirm CCM parameters' potential to differentiate MS patients from healthy subjects, not being influenced by a previous ON history. A significant relationship between patient's disability and corneal nerve morphology was also found. [ABSTRACT FROM AUTHOR]

There has been a growing application of in vivo confocal microscopy (IVCM) in the examination of corneal microstructure, including different corneal layers and corneal nerve fibers in health and in pathological conditions. Corneal nerves forming the sub-basal nerve plexus (SBNP) beneath the corneal basal epithelial cell layer in particular have been intensively researched in health and disease as a marker for corneal neurophysioanatomical and degenerative changes. One intriguing feature in the SBNP that is found inferior to the corneal apex, is a whorl-like pattern (or vortex) of nerves, which represents an anatomical landmark. Evidence has indicated that the architecture of this 'whorl region' is dynamic, changing with time in healthy individuals but also in disease conditions such as in diabetic neuropathy and keratoconus. This review summarizes the known information regarding the characteristics and significance of the whorl region of nerves in the corneal SBNP, as a potential area of high relevance for future disease monitoring and diagnostics. [ABSTRACT FROM AUTHOR]

An automated tool for corneal nerve fiber tortuosity quantification from in vivo confocal microscopy (IVCM) is described and evaluated. The method is a multi-stage process based on the splitting of the corneal nerve fibers into individual segments, whose endpoints are an extreme or intersection of white pixels on a binarized image. Individual segment tortuosity is quantified in terms of the arc-chord ratio. Forty-three IVCM images from 43 laser-assisted in situ keratomileusis (LASIK) surgery patients were used for evaluation. Images from symptomatic dry eye disease (DED) post-LASIK patients, with (n=16) and without (n=7) ocular pain, and non-DED post-LASIK controls (n=20) were assessed. The automated tortuosity measure was compared to a manual grading one, obtaining a moderate correlation (Spearman’s rank correlation coefficient = 0.49, p=0.0008). The new tortuosity index was significantly higher in post-LASIK patients with ocular pain than in control patients (p=0.001), while no significant differences were detected with manual measurement (p>0.28). The tortuosity quantification was positively correlated with the ocular surface disease index (OSDI) and a numeric rating scale (NRS) assessing pain (p=0.0012 and p=0.0051, respectively). The results show good performance of the proposed automated methodology for the evaluation of corneal nerve tortuosity.

Purpose: The aim of this study is to determine age-related morphological changes in the corneal subbasal nerve plexus (SNP) in two inbred mouse strains. Materials and methods: The corneal SNP was investigated by in vivo confocal laser scanning microscopy (CLSM) in 0.5-, 1-, 1.5-, and 2-year-old C57BL/6J mice and in 0.5- and 1-year-old BALB/c mice (n= 4 per age category and strain; 10 images per mouse). Fixed corneal samples from C57BL/6J mice were also analyzed after PGP9.5 staining. Nerve fiber density (NFD) was determined using the semi-automated NeuronJ program. In addition, a new custom-designed, fully automated computerized technique based on oriented multiscale matched filtering was tested to objectify and accelerate image analysis. Results: C57BL/6J mice showed low NFD (11.7 ± 0.5 mm/mm2). Aging from 0.5 to 1, 1.5, and 2 years resulted in significant reductions in subbasal NFD by 34%, 49%, and 66%, respectively. The decline in nerve fibers revealed by in vivo CLSM together with NeuronJ quantification was confirmed by ex vivo immunohistochemical analyses. Subbasal NFD in BALB/c mice (30.0 ± 1.4 mm/mm2) was 3-fold higher than in C57BL/6J mice. Aging from 0.5 to 1 year resulted in a significant 17% reduction in NFD. With the automated approach, NFD of 22.6 ± 2.9 mm/mm2and a 45% reduction during aging was determined from the same images. Conclusions: An age-related reduction in subbasal corneal nerve fibers was observed. The differing extent of reduction in the two mouse strains may be accounted for by genetic factors. Automated NFD quantification of corneal nerve fibers in mice appears to be a useful, reliable, objective, and time-saving tool. [ABSTRACT FROM AUTHOR]

Corneal nerves are of great interest to clinicians and scientists due to their potential for the diagnosis of early neurological disorders. In vivo confocal microscopy (IVCM) has been used as a novel and reliable tool for observing and quantifying corneal sub-basal nerves. Creating a wide-field montage of the nerve plexus from a large amount of IVCM images facilitates the measurement of corneal nerve morphology. In this paper, we propose a fully automatic image stitching method using neural networks. Firstly, we extend a self-supervised point detector to find the feature points on IVCM images. Then a flexible points correspondence based on the attention mechanism is developed for partial assignment of image pair. The scattered IVCM images are consequently integrated and fused according to the local offsets. We experimented with our method on 30 sets of IVCM images. Compared to conventional methods, our method improves matching accuracy and significantly reduces processing time. And by calculating the morphological parameters of the corneal nerve for both single images and stitched images, our method can evaluate the corneal nerve of patients more accurately and reliably. The implemented code is available at https://github.com/LiTianYu6/NerveStitcher., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: To evaluate in vivo parameters as biomarkers of limbal stem cell function and to establish an objective system that detects and stage limbal stem cell deficiency (LSCD)., Methods: A total of 126 patients (172 eyes) with LSCD and 67 normal subjects (99 eyes) were included in this observational cross-sectional comparative study. Slit-lamp biomicroscopy, in vivo laser scanning confocal microscopy (IVCM), and anterior segment optical coherence tomography (AS-OCT) were performed to obtain the following: clinical score, cell morphology score, basal cell density (BCD), central corneal epithelial thickness (CET), limbal epithelial thickness (LET), total corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and tortuosity coefficient. Their potential correlations with the severity of LSCD were investigated, and cutoff values were determined., Results: An increase clinical score correlated with a decrease in central cornea BCD, limbal BCD, CET, mean LET, maximum LET, CNFL, CNFD, CNBD, and tortuosity coefficient. Regression analyses showed that central cornea BCD, CET and CNFL were the best parameters to differentiate LSCD from normal eyes (Coef = 3.123, 3.379, and 2.223; all p < 0.05). The rank correlation analysis showed a similar outcome between the clinical scores and the central cornea BCD (ρ = 0.79), CET (ρ = 0.82), and CNFL (ρ = 0.71). A comprehensive LSCD grading formula based on a combination of these parameters was established., Conclusions: A comprehensive staging system combining clinical presentation, central cornea BCD, CET, and CNFL is established to accurately and objectively diagnose LSCD and stage its severity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)